In recent years, there has been increasing recognition that individuals with T2DM suffer from exacerbated P. aeruginosa infections[47–49]. However, these studies have primarily focused on statistical analysis of clinical data, and there is a need to further explore the underlying molecular mechanisms.
Acarbose is an effective postprandial blood glucose reducer and is widely applied in the clinical treatment of T2DM[33, 50, 51]. Recent studies have reported on the alleviating effects of acarbose on respiratory tract infections and inflammatory responses[35, 38, 52, 53]. However, compared to other clinically used antidiabetic drugs[54, 55], there is currently relatively little research on the impact and mechanism of acarbose in respiratory tract infections in T2DM individuals.
Our study confirmed, using an animal model, that T2DM can exacerbate the severity of P. aeruginosa respiratory tract infections and increase mortality risk, which is consistent with previous clinical data and experimental results[22–26]. Additionally, the study found that acarbose treatment can alleviate the severity of P. aeruginosa respiratory tract infection in T2DM mice, reduce their mortality, and surprisingly, exhibit a certain degree of anti-infective effect in nondiabetic mice with P. aeruginosa respiratory tract infection.
The NF-κB signaling pathway plays a crucial role in the survival of P. aeruginosa within cells, and its initial acute infection can trigger the activation of this pathway. Long-term activation of the NF-κB signaling pathway may contribute to chronic persistent inflammation and long-term colonization of P. aeruginosa [56–58]. Our study discovered that the NF-κB signaling pathway was significantly activated in T2DM mice after P. aeruginosa infection, compared to that in nondiabetic mice. This activation is significantly correlated with the less effective immune response against P. aeruginosa infection in individuals with T2DM, leading to persistent infection and inflammation.
TREM-1 signal activation amplifies the inflammatory response caused by bacterial infection, and blocking its signal transduction can prolong the survival of mice infected with P. aeruginosa[59]. Therefore, the Diabetes + Infected group showed significant activation of the TREM-1 signaling pathway compared with the Ctrl + Infected group, likely exacerbating the infection. The activation of the TREM-1 signaling pathway, along with the activation of the NF-κB signaling pathway and pathogen-induced cytokine storm signaling pathway, collectively mediates the exacerbation of P. aeruginosa respiratory tract infection in T2DM mice. Notably, the predicted activation of these signaling pathways is closely associated with the upregulation of IL-1β, IL-6, and TNF-α expression. In summary, our study effectively explores the impact of T2DM on P. aeruginosa respiratory tract infection and its possible mechanisms, providing potential therapeutic targets for controlling this complex disease condition.
HIF-1α is an effective regulator of innate immunity that can inhibit the innate immune response of airway epithelial cells and promote bacterial infection, while P. aeruginosa secreted factors significantly inhibit its function[60–63]. Our study found that the inhibition of the HIF-1α signaling pathway may be associated with the inhibitory and prognostic improvement effects of acarbose on P. aeruginosa respiratory tract infection in T2DM mice. However, another study has shown that HIF-1 knockout in Caenorhabditis elegans can exacerbate the pathogenesis of P. aeruginosa[64]. In future studies, we will further determine the role of the HIF-1α signaling pathway in P. aeruginosa infection and explore its mechanism.
It is noteworthy that our study found that oral acarbose had a therapeutic effect on P. aeruginosa respiratory tract infection in both diabetic and nondiabetic mice. Following acarbose treatment, the calcium signaling pathway was inhibited in nondiabetic mice with P. aeruginosa respiratory tract infection, which is different from the mechanistic changes observed in T2DM mice. Previous studies suggest that P. aeruginosa activates the calcium ion signaling pathway, activating the inflammatory signal and causing excessive airway inflammation[65, 66]. Therefore, the calcium ion signaling pathway inhibition in this section's experimental results may be associated with acarbose's ability to alleviate P. aeruginosa infection in nondiabetic mice.
Additionally, our study discovered that both T2DM and nondiabetic mice with P. aeruginosa respiratory tract infection showed significant inhibition of the NF-κB signaling pathway following acarbose treatment. The inflammatory response mediated by NF-κB is the primary pathway induced by P. aeruginosa infection[57, 58, 67]. Therefore, acarbose may be able to alleviate P. aeruginosa respiratory tract infection severity in mice by inhibiting the NF-κB signaling pathway, independent of blood glucose levels.
In previous studies, the mechanism of action of antidiabetic drugs against infection has mainly been investigated based on their hypoglycemic effects[35, 52]. However, our study demonstrated that acarbose not only has an inhibitory effect on P. aeruginosa respiratory tract infection in T2DM mice but also in nondiabetic mice, indicating an anti-infective function independent of blood glucose and lung glucose levels. Moreover, we observed that the molecular mechanisms of acarbose against P. aeruginosa respiratory tract infection in T2DM and nondiabetic mice are not completely identical. This may be because acarbose has some degree of potential to help fight respiratory tract infections, as previously discovered in its potential use for COVID-19 patients. Our future studies will focus on modulating the activation or inhibition of the aforementioned signaling pathways to explore their specific causal effects on these diseases.
In summary, our study found that (1) the exacerbation of P. aeruginosa respiratory tract infection in T2DM is attributed to the activation of the NF-κB and TREM-1 signaling pathways, (2) the alleviation of P. aeruginosa respiratory tract infection by acarbose in T2DM individuals is related to the inhibition of the NF-κB and HIF-1α signaling pathways, and (3) this alleviation in nondiabetic individuals is associated with inhibiting the NF-κB and calcium signaling pathways. Our study identifies the preventive and therapeutic effects of acarbose in respiratory tract P. aeruginosa infection in both T2DM and nondiabetic individuals and explores its potential mechanisms, providing new support for its clinical application as an anti-infective or adjuvant medication.